P21-activated kinase 1 (Paki), a major mitocen-responsive signaling nodule, is upregulated in human breast cancer. Despite the remarkable growth of information about the role of Pakl in human cancer, remains unknown whether Paki or its direct targets participate in the DNA damage response pathway and thus, could influence the responsiveness cancer cells to radiation therapy - one the major treatment regimens currently used for cancer treatment Our preliminary studies have discovered for the first time that clinically relevant dose of DNA damage stimulates the nuclear Pakl activity and that a novel Pakl substrate MORC, is required for optimal stimulation of gamma-H2AX and survival of breast cancer cells in a Paki -phosphorylation dependent manner. This proposal represents a continuing interest of the P1 to define the significance of Paki its effectors in human breast cancer. Here we propose to investigate the role of the Pakl-MORC pathway as a new player to the growing network of DNA damage response mechanisms in human breast cancer cells. Our preliminary studies have allowed us to suggest that Pakl signaling plays an inherent role in efficient DNA damage responsiveness and that MORC acts as a modifier/signaling component for efficient activation of gamma-H2AX. Our testable working hypothesize is that "DSB stimulates nuclear Paki activity and that Paki signaling contributes to DNA damage response via phosphorylating MORC nuclear protein." Regulation of Pakl-MORC pathway may have significant consequences relating to the sensitivity versus resistance of breast cancer cells and could be potentially exploited to develop novel combination therapies, co-targeting of Paki and/or MORC. To address these hypotheses, our Specific Aims are to determine: (1) The mechanistic basis of Paki stimulation by DSB damage and role of Paki in DSB signaling in breast cancer cells;(2) The molecular basis and significance of MORC's contribution in DNA damage response. An innovative aspect of our proposal is the focus on molecules with established roles in cancer cells. It is our hope that the knowledge gained from this project will form the basis for new mechanistic advances in DNAdamage response in breast cancer cells.